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Career Development Panel Presentation:
The Historical Context of Clinical Research
Medical research had gone on for many years largely unregulated despite the fact that philosophers had been discussing the need to protect the safety and welfare of the human research subject volunteer. As far back as ancient Egypt, the first century physician, Celsius, justified medical experimentation on condemned criminals using the words which lived on to become the classic defense for hazardous experimentation: "It is not cruel to inflict on a few criminals sufferings which may benefit multitudes of innocent people through all centuries."
Today, people who step forward to volunteer in a drug study are safer than ever before. There are tremendous efforts by multiple groups to protect the safety and welfare of those who are good enough to stand up and decide to go first and try a new experimental treatment. It is our task now to point out what a Doctor that chooses a career path in Pharmaceutical Medicine as a Pharmaceutical Physician should know about the historical context of clinical research in order to preserve the rights, dignity and welfare of the patients that volunteer to be research subject volunteers.
As research tragedies have occurred over the years, legislation aimed at preventing their reoccurrence has ensued. This is sort of like the saying, "As the branch bends, the tree grows." Well, in medical research, as mistakes happened, we have been reactionary in legislating changes to prevent these mistakes from happening again. This is why the history of medical research is such an important topic in a career development panel discussion such as this one. For, if we don't know history, we are bound to repeat it!
In the late 1800s in America, medicine and pharmacology were made up largely of folklore, charlatans, alternative medicine and patent medicines. Numerous accounts of "snake oil salesmen" abounded. To become a bona fide patent medicine, all one had to do was patent the ingredients. There were no considerations for: purity, safety nor efficacy. The ingredients were considered "secret" and never listed on the label. Those medicines seemed to treat "what ails ya" without any side effects. In 1820, eleven physicians met in Washington, DC to establish the US Pharmacopeia, the first compendium of standard drugs for the United States. In 1862, President Lincoln appointed a chemist, Charles M. Wetherill, to serve in the new Department of Agriculture. This was the beginning of the Bureau of Chemistry, the predecessor of the Food and Drug Administration.
On June 30, 1906, the Pure Food and Drug Act was first enacted. It created the Food, Drug and Insecticide Administration in Washington, DC, whose name was shortened in 1930 under an agricultural appropriations act to the Food and Drug Administration (FDA). It said certain drugs could only be sold by prescription and had to be proven "pure"; that is it had to have what it claimed to have in it. This law came about as a result of an exposť written by Upton Sinclair entitled The Jungle. In it he exposed the horrible sanitary conditions that were part and parcel of the meat packing industry in that era. It failed to provide for safety or efficacy, however.
In 1938, the Food, Drug and Cosmetic Act was passed. Now, for the first time, prescription drugs needed to be proven "safe." That is, before 1938, the law only mandated the drugs were pure. There was no thought that they should be tested first to prove their safety. This law was enacted as a reaction to the 1937 Massengil Drug Company sulfanilamide antibiotic tragedy. They released a flu treatment that contained antifreeze. They followed the law of the day and listed it in the ingredients without checking to see if it was safe. It caused acute renal failure in an era before there was hemodialysis and 107 people, mostly children, died. The public outcry caused the act to pass in 1938 to prevent another tragedy like this from occurring.
In 1962, the Kefauver-Harris Amendments were added now requiring for the first time that drugs be proven "effacious" besides pure and safe. That is, prior to making it all the way to the marketplace, drug studies were required to be performed showing that this brand new treatment actually works! This law was also enacted as a reaction to the 1961 thalidomide tragedy where over 300 infants were born with phocomelia, a birth defect where they are missing extremities. Apparently, the PIs in the 1960s were giving out "free samples" of the study drug, thalidomide to pregnant women to treat morning sickness who were not even enrolled in the study. It then became necessary to give the study drug only to study participants.
The following are some important "research errors" that have occurred:
The Tuskegee Syphilis Study began in 1932 enrolling poor black men with syphilis in a drug trial where they didn't receive any drug and were told lies about the efficacy of the treatment. This was further exacerbated by deliberately withholding and preventing them from receiving penicillin when it was invented in 1942. The study was ended in 1972 when a reporter exposed the story. President Clinton issued a formal apology in 1997.
Between 1944 and 1974, the government sponsored several thousand human radiation experiments using doses likely to do harm to unsuspecting participants. This research error was exposed finally in 1993. In 1994, President Clinton created the Advisory Committee on Human Radiation Experiments to identify ethical and scientific standards.
In 1947, the international military tribunal in Nuremberg, Germany, tried 26 German physicians for war crimes against humanity for recruiting unwilling prisoners for horrific, fatal medical experiments. The Nuremberg Code was a result of this, which outlined the fundamental ethical principals in human research. It is regarded as the first internationally recognized set of guidelines to help promote safety stating that voluntary consent is an absolute essential.
In 1953, University of Chicago researchers tape-recorded jurors' deliberations without their knowledge. The judge and both sets of lawyers knew. A federal law was passed in 1956 banning all recording of jury proceedings.
In the early 1960s, as Harvard was formulating its policies regarding human research, two of its professors, Timothy Leary and Richard Alpert gave LSD they obtained from Sandoz Pharmaceuticals (it wasn't illegal then) to undergrads. They were both fired.
Also, in the early 1960s, Stanley Milgram's research on obedience to authority harmed subjects by making them believe they were shocking to death their poor performing students.
In Brooklyn, NY, in 1963, Doctors at the Jewish Chronic Disease Hospital (now called Interfaith) injected unconsented subjects with live cancer cells to see if they developed any signs of neoplasia. They then proudly published their results.
Retarded children were given live hepatitis virus at the Willowbrook State School in Staten Island, NY. in the 1960s. The doctors rationalized that the kids were probably going to get it anyway. They unfairly coerced parents to sign the ICFs.
The Beecher Article came out in the 1966 NEJM sighting 22 examples of unethical research conducted and published in reputable journals.
The Tea Room study in the 1960s tracked gay men down using unethical tactics and gave them a social health survey one year later without proper IC.
On March 31, 1996, a 19 year-old Asian-American student, Hoiyan Nicole Wan, at the University of Rochester died of a lidocaine overdose in part of a phase one FOB trial where the protocol didn't place limits on the quantity of lidocaine the pulmonologist could use. The headlines read, "Death of a Normal Volunteer."
In the fall of 1999, medical research saw a death on Gene Therapy Trial with 18 year old Jessie Gelsinger. The PI had a lot of money invested in the sponsor bringing issues of ethical integrity and proper IC to the news. Financial statements of investigators then became the law.
In April 1999 at the VA West LA Medical Center, PIs were enrolling subjects without their knowledge or consent. Some participants actually refused and were still enrolled!
On May 12, 1999, Duke Clinical Research Institute was shut down by the OPRR (Office for Protection from Research Risk) due to problems with its IRB.
On June 2, 2001, Ellen Roche, a 24 year-old healthy volunteer in a phase one trial died in an asthma research trial for failure of the researchers to recognize the dangers of hexamethonium.
So, when you ask a subject to sign an ICF, these events can cause your patient concern. What the PI should point to is the many positive things that where done to ensure subject safety and welfare including:
In 1953, the first IRB came out of an NIH Policy on the protection of human research subject volunteers.
The Declaration of Helsinki: first adopted in 1964 and subsequently updated, makes additional safety recommendations to the Nuremberg Code including preliminary experiments on animals, IRB procedures and DSMBs.
The Public Health Service was created in 1966 providing volunteers with IC via an ICF. This led to expanded role of the IRB as an oversight arm of the research process.
In 1979, the Belmont Report was released by the National Commission for the Protection of Human Subjects of Biomedical and Behavior Research, entitled: Ethical Principles and Guidelines for Research Involving Human Subjects. It identified the three principles: Respect for Persons; Beneficence; and Justice.
In 1980, the FDA established the Code of Federal Regulations (CFR) to establish regulations on the protection of human subjects.
In 1982, CIOMS (Council for the International Organization of Medical Sciences) published the International Ethics Guidelines for Biomedical Research Involving Human Subjects. This is to help guide drug study ethics in third world areas.
In 1989, the PHS (Public Health Service) created the OSI (Office of Scientific Integrity) and the OSIR (Office of Scientific Integrity Review) which were consolidated in May 1992 to the ORI (Office of Research Integrity) to deal with scientific misconduct.
In 1991, The Common Rule 45CFR46 became a federal policy for the protection of human subjects revised in 2001.
In June 1996, ICH-GCP Harmonized tripartite Guideline to provide standards for research among EU, Japan, USA.
In 1997, the Food and Drug Administration Modernization Act further improved regulation of drugs.
In conclusion, when considering a career in pharmaceutical medicine, the pharmaceutical physician can gain a lot from borrowing from the knowledge of the historical context of both negative events and the constant pursuit to improve the drug study process and healthcare.